Alcohol use disorders are a major health and social problem in the United States, with more than 18 million Americans who meet the diagnostic criteria for alcohol abuse or dependence. Both human and animal studies show that genetic and environmental factors, in addition to their interaction, play an important role in the development of alcoholism. The goal of this project is to identify genetic factors related to alcoholism in a mouse model system in order to understand mechanisms and inferred pathways predisposing individuals to the disease. The specific objective of this project is to examine how variation modulated through micro RNA (miRNA) activity and binding affects gene expression regulation in the brains of mice and is associated with alcoholism related traits (or endophenotypes). The LXS mouse panel will form the basis of our work and is a large recombinant inbred panel with has been subject to high-throughput gene expression and high-density genotyping profiling, in addition to extensive behavioral testing. In particular, the examined behavioral endophenotypes will be the predisposition to ethanol sensitivity, tolerance and consumption. To discover potential candidates for miRNA gene regulation, our research aims include the generation of high-throughput miRNA expression profiling data on the LXS panel and the use of novel bioinformatics techniques to integrate these data with the genotyping resources, gene expression data and behavioral testing results. Molecular assays will be performed to validate promising candidates and to localize brain region effects. Generating valuable miRNA data resources on the LXS panel for other investigators will be an important deliverable during the course of the study. To accomplish our objectives, a multidisciplinary investigative team has been assembled with extensive knowledge and experience in alcohol-related behavioral testing in mice, miRNA regulation, gene expression analysis and mouse genetics. At the conclusion of this project, the role of specific miRNA, and respective mRNA, associated with the predisposition to alcohol response and intake will be predicted and validated. These results will give mechanistic insight regarding genetic risk factors for alcoholism, information that can be used in the future for personalized medicine and other therapeutic and diagnostic purposes.